Trifluoroacetic acid → 2-amino-3-cyclopropoxy-N-methoxy-N-methylbenzamide

HRID 595030Notes

Reaction equation

HRID 595030 reaction equation
Cl.CN[O:4][CH3:5].Cl.C(N=C=[N:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:17])C)C.[OH2:18].ON1C2C=[CH:26][CH:27]=[CH:28][C:23]=2N=N1.C(N([CH2:34][CH3:35])CC)C.[C:36](O)(C(F)(F)F)=[O:37]>CN(C=O)C.O.CO>[NH2:11][C:12]1[C:26]([O:4][CH:5]2[CH2:35][CH2:34]2)=[CH:27][CH:28]=[CH:23][C:13]=1[C:14]([N:15]([O:37][CH3:36])[CH3:17])=[O:18]

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrate

Product 1

HCID 900798402-amino-3-cyclopropoxy-N-methoxy-N-methylbenzamideYield 64.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 22242641Methanol--water (1/1)Solvent

Conditions

Temperature
60 °C

Procedure

To a solution of Intermediate A1D (6.61 g, 34.2 mmol) N,O-dimethylhydroxylamine hydrochloride (10.01 g, 103 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.87 g, 41.1 mmol) and 1-hydroxybenzotriazole hydrate (6.29 g, 41.1 mmol) in 50 ml of DMF was added triethylamine (19.07 mL, 137 mmol). The reaction solution was stirred at 60° C. overnight and then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate and transferred to a separatory funnel and washed with 10% LiCl, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a dark oil. The crude product mixture was purified via silica gel chromatography (hexanes/EtOAc) to give Intermediate A1E (5.2 g, 22.01 mmol, 64.3% yield). HPLC: RT=1.975 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=237.12 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.17 (dd, J=8.0, 1.2 Hz, 1H), 7.02 (dd, J=7.9, 1.3 Hz, 1H), 6.67 (t, J=7.9 Hz, 1H), 4.78 (br. s., 2H), 3.88-3.73 (m, 1H), 3.69-3.56 (m, 3H), 3.36 (s, 3H), 0.92-0.72 (m, 4H)).

Workup

  1. temperaturecooled to room temperature
  2. customThe reaction mixture was partitioned between water and ethyl acetate
  3. customtransferred to a separatory funnel
  4. washwashed with 10% LiCl, water, and brine
  5. dry with materialThe organic phase was dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto provide a dark oil
  9. customThe crude product mixture was purified via silica gel chromatography (hexanes/EtOAc)
  10. customto give Intermediate A1E (5.2 g, 22.01 mmol, 64.3% yield)

Sources & evidence

ORD record
ord-2bae087de2ec424aade7141b9090b623
Source dataset
uspto-grants-2016_01
Patent number
US09242941B2

Reaction notes

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